The ADP-ribose reactive NUDIX hydrolase isoforms can modulate HIF-1α in cancer cells.

The human nucleoside-diphosphate linked moiety-X (NUDIX) hydrolases that utilize ADP-ribose and NADH/NAD⁺ are overexpressed in cancer cells, but their roles in hypoxia inducible factor-1α (HIF-1α) regulation have not yet been revealed. Here, we showed that these NUDIX hydrolases negatively regulated HIF-1α accumulation by modulating the Ca²⁺ dependent AMP-activated protein kinase (AMPK) signaling pathway. In specific, knockdown of NUDT9 resulted in accumulation of free ADP-ribose that triggered Ca²⁺ influx mediated by transient receptor potential cation channel subfamily M member 2 and subsequent activation of Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ). In addition, AMPK activation by CaMKKβ was shown to enhance HIF-1α accumulation. Our findings provide insights into the action of NUDIX hydrolases as an additional, discrete modulator of HIF-1α accumulation.

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